Temozolomide Chronotherapy for High Grade Glioma

June 17, 2025 updated by: Washington University School of Medicine

A Randomized Feasibility Study Evaluating Temozolomide Chronotherapy for High Grade Glioma

Temozolomide (TMZ) is the chemotherapy drug approved by the FDA to increase survival in glioblastoma (GBM) patients beyond surgical resection and radiation therapy alone. Give its activity in astrocytomas, TMZ is commonly used in grade III anaplastic astrocytoma (AA) as well. Both grade III AA and grade IV GBM are high grade gliomas (HGG). The short half-life of this drug and known oscillations in DNA damage repair make it an ideal candidate for chronotherapy.

Chronotherapy is the improvement of treatment outcomes by minimizing treatment toxicity and maximizing efficacy through delivery of a medication according to the timing of biological rhythms within a patient. Chronotherapy has improved outcomes through the reduction of side effects and increase in anti-tumor activity for a variety of cancers, but has never been applied to the treatment of gliomas.

Based on the preliminary preclinical data for chronotherapeutic TMZ treatment of intracranial glioma xenografts and the success of chronotherapy in the treatment of other cancers, the investigators hypothesize that the timing of TMZ treatment will alter its efficacy and toxicity.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

42

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University School of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Newly diagnosed and recurrent high grade gliomas (WHO grades III & IV) and high risk WHO grade II gliomas who are to begin treatment with monthly high dose temozolomide therapy.
  • Scheduled to receive adjuvant temozolomide therapy after having completed concurrent temozolomide and radiation therapy.
  • At least 18 years of age.
  • Karnofsky performance status ≥ 60%
  • Ability to understand and willingness to sign an IRB approved written informed consent document

Exclusion Criteria:.

-Pregnant and/or breastfeeding. Women of childbearing potential must have a negative pregnancy test within 14 days of study entry.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Arm 1: Temozolomide morning
  • Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m^2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the morning (before 10:00).
  • FACT-Br quality of life at baseline, at the beginning of each cycle of chemotherapy, and 1 month after the final chemotherapy treatment
Drug: Temozolomide
-Given standard of care
Other Names:
  • Temodar
Other: Functional Assessment of Cancer Therapy - Brain
  • 23-item questionnaire that can be completed in 5 to 10 minutes with little or no assistance in patients who are not neurologically incapacitated. This brain subscale is usually used along with the core (general) questionnaire [2] that includes 27 items.
  • Patients rate all 5 items using a five-point Likert scale ranging from 0 "not at all" to 4 "very much." Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items)
  • The sleep portion of this questionnaire consists of 17 questions about sleeping patterns and the ability to rate severity of insomnia.
Other Names:
  • FACT-Br
Other: ActTrust Condor Instrument Watch
-Will be required to wear 24 hours per day and will only be removed at specified data collection time points
Experimental: Arm 2: Temozolomide evening
  • Temozolomide will be given as per standard of care. Typical dosing is 150 to 200 mg/m2 on Days 1 through 5 of a 28-day treatment cycle. Patients will be randomized to take their temozolomide doses in the evening (after 20:00).
  • FACT-Br quality of life at baseline, at the beginning of each cycle of chemotherapy, and 1 month after the final chemotherapy treatment
Drug: Temozolomide
-Given standard of care
Other Names:
  • Temodar
Other: Functional Assessment of Cancer Therapy - Brain
  • 23-item questionnaire that can be completed in 5 to 10 minutes with little or no assistance in patients who are not neurologically incapacitated. This brain subscale is usually used along with the core (general) questionnaire [2] that includes 27 items.
  • Patients rate all 5 items using a five-point Likert scale ranging from 0 "not at all" to 4 "very much." Overall, higher ratings suggest higher QOL. Items are totaled to produce the following subscales, along with an overall QOL score: physical well-being (7 items); social/family well-being (7 items); emotional well-being (6 items); functional well-being (7 items); and concerns relevant to patients with brain tumors (23 items)
  • The sleep portion of this questionnaire consists of 17 questions about sleeping patterns and the ability to rate severity of insomnia.
Other Names:
  • FACT-Br
Other: ActTrust Condor Instrument Watch
-Will be required to wear 24 hours per day and will only be removed at specified data collection time points

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Feasibility of Patient Treatment Compliance as Measured by Number of Participants Who Were at Least 80% Compliance With Assigned Administration Time
Time Frame: Through completion of treatment (median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)
Compliance is defined as no more than one of five doses of temozolomide per cycle taken outside of the assigned administration time.
Through completion of treatment (median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)
Duration of Response
Time Frame: Through completion of follow-up (estimated to be 30 months)
  • Response and progression will be evaluated in this study using the updated response assessment criteria for high-grade gliomas: Response Assessment in Neuro-Oncology (RANO) working group guideline [JCO 28(11): 1963-1972, 2010].
  • The duration of overall response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
Through completion of follow-up (estimated to be 30 months)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Patients Experiencing Grade 3 or 4 Lymphopenia, Thrombocytopenia, Neutropenia, Leukopenia, and Anemia in Each Group as Measured by Standard Blood Draws
Time Frame: Through completion of treatment (median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)
  • Lymphopenia grade 3 is <500-200/mm^3 and grade 4 is <200/mm^3
  • Leukopenia grade 3 is <2000-1000/mm^3 and grade 4 is <1000/mm^3
  • Neutropenia grade 3 is <1000-500/mm^3 and grade 4 is <500/mm^3
  • Thrombocytopenia grade 3 is <50,000-25,000/mm^3 and grade 4 is <25,000/mm^3
  • Anemia grade 3 is <8.0-6.5 g/dL and grade 4 is <6.5 g/dL
Through completion of treatment (median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles)
Change in Quality of Life as Measured by FACT-Br Score - Physical Well-being Score
Time Frame: Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
7-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range is 0-28. A higher score indicates a lower physical well-being quality of life.
Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
Change in Quality of Life as Measured by FACT-Br Score - Social/Family Well-being Score
Time Frame: Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
7-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range 0-28. A higher score indicates a higher social/family well-being quality of life.
Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
Change in Quality of Life as Measured by FACT-Br Score - Emotional Well-being Score
Time Frame: Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
6-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range 0-24. A higher score indicates a lower emotional well-being quality of life.
Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
Change in Quality of Life as Measured by FACT-Br Score - Functional Well-being Score
Time Frame: Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
7-item questionnaire measuring over the past 7 days. Answers range from 0=not at all to 4=very much. Total score range 0-28. A higher score indicates a higher emotional well-being quality of life.
Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
Median Progression-free Survival (PFS)
Time Frame: Through completion of follow-up (median length of follow-up 568.5 days, full range 1-1134 days)
PFS is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
Through completion of follow-up (median length of follow-up 568.5 days, full range 1-1134 days)
Median Overall Survival
Time Frame: Through completion of follow-up (median length of follow-up 568.5 days, full range 1-1134 days)
Through completion of follow-up (median length of follow-up 568.5 days, full range 1-1134 days)
Comparison of Sleep Questionnaire in Participants Receiving Temozolomide in the Morning Versus Participants Receiving Temozolomide in the Evening
Time Frame: Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
Sleep Questionnaire - 1 yes/no question of "do you have problems getting to sleep or staying asleep?"
Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
Comparison of Sleep Questionnaire in Participants Receiving Temozolomide in the Morning Versus Participants Receiving Temozolomide in the Evening
Time Frame: Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))

- Sleep Questionnaire:

  • Difficulty falling asleep/difficulty staying asleep/problem waking up too early: Answers range from 0=none, mild=1, moderate=2, severe=3, very=4.
  • How satisfied or dissatisfied are you with your current sleeping pattern question: Answers range from 0=very satisfied to 4=very dissatisfied.
  • To what extent do you consider your sleep problem to interfere with your daily functioning question: Answers range from 0=not at all interfering, 1=a little, 2=somewhat, 3=much, 4=very much interfering.
  • How noticeable to others do you think your sleep problem is in terms of impairing the quality of your life question: Answers range from 0=not at all noticeable, 1=barely, 2 = somewhat, 3 =much, 4=very noticeable.
  • How worried or distressed are you about your current sleep problem question: Answers range from 0=not at all=0, 1=a little, 2=somewhat, 3=much, 4=very much.
Baseline, beginning of each cycle (each cycle is 28 days), and 1 month after completion of treatment (up to 13 months, median length of treatment 6 cycles - each cycle is 28 days (full range 2-12 cycles))
Mean Circadian Amplitude
Time Frame: From start of treatment through 2 months after end of treatment (median length 100 days, full range 78-240 days)
  • The ActTrust Condor Instrument watches are wrist actimetry/accelerometers. Patients will wear an accelerometer on their wrist to measure activity level during the day and at night until two months after the end of treatment.
  • Circadian amplitude, refers to the difference between the highest and lowest points of a circadian rhythm over a 24-hour cycle, is typically measured in the units of the rhythm being quantified.
  • The circadian mean amplitude was calculated per day for each patient with the mean and standard deviation reported across all days for each individual patient.
From start of treatment through 2 months after end of treatment (median length 100 days, full range 78-240 days)
Mean Sleep Regularity Index (SRI)
Time Frame: From start of treatment through 2 months after end of treatment (median length 100 days, full range 78-240 days)
  • The ActTrust Condor Instrument watches are wrist actimetry/accelerometers. Patients will wear an accelerometer on their wrist to measure activity level during the day and at night until two months after the end of treatment.
  • Sleep regularity index (SRI) is the probability of being at rest, calculated per day for each patient. An SRI closer to 0 indicates irregular sleep patterns (i.e., more variable day to day), while values closer to 1 indicate regular sleep patterns. The SRI index scale is 0~1.
  • The SRI was calculated per day for each patient with the mean and standard deviation reported across all days for each individual patient.
From start of treatment through 2 months after end of treatment (median length 100 days, full range 78-240 days)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Washington University School of Medicine

Investigators

  • Principal Investigator: Milan Chheda, M.D., Washington University School of Medicine

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 11, 2016

Primary Completion (Actual)

July 18, 2024

Study Completion (Actual)

July 18, 2024

Study Registration Dates

First Submitted

May 20, 2016

First Submitted That Met QC Criteria

May 20, 2016

First Posted (Estimated)

May 24, 2016

Study Record Updates

Last Update Posted (Actual)

June 27, 2025

Last Update Submitted That Met QC Criteria

June 17, 2025

Last Verified

June 1, 2025

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201605081

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Subscribe